REVIEWARTICLE

Neuroimaging of Rapidly Progressive Dementias,Part 1: Neurodegenerative Etiologies

A.J. Degnan and L.M. Levy

ABSTRACT

SUMMARY: Most dementias begin insidiously, developing slowly and generally occurring in the elderly age group. The so-calledrapidly progressive dementias constitute a different, diverse collection of conditions, many of which are reversible or treatable. Forthis reason, prompt identification and assessment of acute and subacute forms of dementia are critical to effective treatment.Numerous other entities within this category of presenile rapid-onset dementias are untreatable such as the prion-related diseases.Neuroimaging aids in the diagnosis and evaluation of many of these rapidly progressive dementias, which include myriad conditionsranging from variations of more common neurodegenerative dementias, such as Alzheimer disease, dementia with Lewy bodies, andfrontotemporal dementia; infectious-related dementias such as acquired immune deficiency syndrome dementia; autoimmune andmalignancy-related conditions; to toxic and metabolic forms of encephalopathy. This first of a 2-part review will specifically addressthe ability of MR imaging and ancillary neuroimaging strategies to support the diagnostic evaluation of rapidly progressive dementiasdue to neurodegenerative causes.

ABBREVIATIONS: AD � Alzheimer disease; CBD � corticobasal degeneration; DLB � dementia with Lewy bodies; HD � Huntington disease; MSA � multiple-system atrophy; PSP� progressive supranuclear palsy

With the increase of the aging population in the United

States, the accurate recognition of dementia types is be-

coming an important clinical topic. Dementia is marked by cog-

nitive decline, loss of normal memory function, and impairment

in judgment without disruption of consciousness. Clinical histo-

ry-taking, laboratory investigation, and imaging studies should be

used with the aim of ascertaining dementia diagnoses related to

reversible causes and etiologies amenable to treatment and deter-

mining the prognosis for irreversible and progressive illnesses.

Unlike their more typical counterparts, rapidly progressive de-

mentias are also more frequently atypical and heterogeneous in

their clinical presentation, necessitating the use of additional di-

agnostic measures, including MR imaging, to improve diagnosis

when the clinical situation is tenuous.

Thorough clinical evaluation and laboratory investigation are

fundamental for ascertaining progressive dementias, especially

those of more acute onset and in presenile patients (those younger

than 65 years of age). Laboratory investigations are vital in determin-

ing several of the illnesses within the differential diagnosis of a rapid-

onset dementia, which, for the purposes of this review, is generally 6

months from onset of symptoms to fulminant dementia. As noted in

the differential diagnosis On-line Table, rapidly progressive demen-

tias may present with a wide variety of manifestations and etiologies.

Other forms of rapidly progressive dementia, however, are

better characterized by using advanced imaging methods such as

MR imaging; 1 study of rapidly progressive dementias noted that

MR imaging findings suggested the specific diagnosis in one-third

of cases.1 Several excellent clinical reviews of the subject discuss

the features of rapidly progressive dementias with supportive lab-

oratory and clinical evaluations, which are abbreviated in this

neuroimaging-focused review.2-4

Neurodegenerative DementiasMost dementias in general are neurodegenerative, most com-

monly of the Alzheimer type, though there is increasing awareness

with greater imaging and more thorough investigations of non-

Alzheimer disease–related dementias.2 A review of cases from a

referral center for suspected prion disease showed that neurode-

generative disease makes up the largest portion of nonprion diag-

noses.4 Conditions within this category generally present with a

protracted clinical course of gradual decline in cognitive function.

However, genetic variants of several neurodegenerative demen-

From the University of Pittsburgh Medical Center (A.J.D.), Pittsburgh, Pennsylvania;and Department of Radiology (L.M.L.), George Washington University Hospital,Washington, DC.

Please address correspondence to Lucien M. Levy, MD, 901 23rd St NW, Washing-ton, DC 20037; e-mail: llevy@mfa.gwu.edu

Indicates open access to non-subscribers at www.ajnr.org

Indicates article with supplemental on-line table.

http://dx.doi.org/10.3174/ajnr.A3454

AJNR Am J Neuroradiol ●:● ● 2014 www.ajnr.org 1

Published March 21, 2013 as 10.3174/ajnr.A3454

Copyright 2013 by American Society of Neuroradiology.

tias may present much more rapidly than their prototypical

presentations.

Early-Onset Alzheimer Disease. Unlike its more common form,

early-onset AD is characterized by a much shorter time course

and greater anatomic and functional alterations.2 Imaging find-

ings in early-onset AD are also slightly different from those in

senile AD, with a higher magnitude of atrophy within the occipital

and parietal lobes.5 This change is in lieu of the stereotypical hip-

pocampal atrophy; however, the imaging findings common in AD

in general may be observed in cases of early onset, which are

discussed at greater depth elsewhere.6 Medial temporal lobe atro-

phy appears to be a great discriminator of AD versus dementia

with Lewy bodies and vascular-related cognitive decline.7 Imag-

ing findings within certain subtypes of AD are based on genetic

syndromes such as those with a presenilin-1 mutation that mani-

fests white matter changes (hyperintense on FLAIR) atypical of

AD.8,9

In AD, MR spectroscopy may aid in the diagnosis, with a no-

table decrease in N-acetylaspartate and an increase in myo-inosi-

tol and choline in patients with AD and those with presymptom-

atic AD.10,11 While it is outside the scope of this review, positron-

emission tomography may offer added diagnostic acumen in

recognizing AD with the use of the newly FDA-approved florbeta-

pir F18 injection (Amyvid; Eli Lilly, Washington, DC), which spe-

cifically binds to �-amyloid.12 Effort is also being directed at de-

veloping appropriate targeted MR imaging contrast agents.

As reviewed at greater length elsewhere, several advanced MR

imaging techniques may be useful in making the diagnosis of

AD.2,13 DTI is the subject of numerous active research studies and

beyond the scope of this focused review. In brief, there is some

evidence that DTI shows increased diffusivity within the temporal

lobe in AD and may aid in differentiating it from other dementias

such as dementia with Lewy bodies.14 Magnetization transfer im-

aging is one of the latest imaging methods to be applied to AD.

Histopathologic information may be inferred from this method

in light of the correlation between magnetization transfer ratio

and the extent of axonal loss, and these changes may proceed to

gross volume loss.2

Dementia with Lewy Bodies. DLB accounts for a small fraction

of presenile-onset dementia syndromes, constituting only ap-

proximately 4% of presenile dementias, but its rapidity of decline

with an average survival of 3 years places it in the differential

diagnosis of rapidly progressive dementias.2,3,15 Frequently, neu-

rologic symptoms in DLB are nonspecific and analogous to other

neurodegenerative diseases. Because findings are nonspecific in

DLB (such as atrophy within gray matter of the temporal, parietal,

and occipital lobes), conventional MR imaging is of greatest ben-

efit in ruling out other causes of rapidly progressive dementia

rather than diagnosing DLB specifically.16 Relative preservation

of the medial temporal lobe has been one of the few consistent

findings of volumetric structural studies; another key difference

compared with AD is the preservation of the NAA-to-creatine

ratios on MR spectroscopy.17,18 Recent attempts have been made

to differentiate DLB from AD, and one such study has noted a

lower fractional anisotropy within the white matter of the post-

central gyrus, which correlated with decreased motor function

clinically.14 Using DTI, Bozzali et al19 noted decreased fractional

anisotropy in many white matter regions, with relatively modest

involvement of the temporal lobe. Another recent study by Bur-

ton et al16 reported reduced amygdala volume as a possible

marker of DLB that correlates with the presence of Lewy bodies on

pathology. Although outside the scope of this MR imaging– based

review, reduced dopamine transporter levels in DLB, as shown

with iodine 123 N-(3-fluoropropyl)-2�-carbomethoxy-3�-(4-

iodophenyl)-nortropane SPECT, might assist in the diagnosis of

DLB in light of the currently limited role for MR imaging.20

Frontotemporal Dementia. Frontotemporal dementia, albeit

generally with quicker symptom progression than AD, is a rarer

form of rapidly progressive dementia.3 Moreover, some clinical

attributes differentiate it from many other dementias, with a

prominence of personality changes and impaired sociability. Im-

aging can demonstrate the atrophy for which this condition is

named in half of the cases, though early phases of this condition

may be missed and imaging is used with the primary purpose of

excluding other forms of dementia.2,21 The “knife edge” sign is

one imaging finding supportive of frontotemporal dementia on

MR imaging and is described as focal atrophy within the anterior

temporal lobe at the level of the temporal horn of the lateral ven-

tricle.21,22 One study integrating MR imaging and clinical mea-

sures of dementia demonstrated associations between worsening

of these rating scales and rates of ventricular expansion and

whole-brain volume loss.23

Corticobasal Degeneration. Because CBD may present clinically

with progressive dementia and some of the rare neurologic symp-

toms seen in Creutzfeldt-Jakob disease, such as alien limb and

myoclonus, imaging is essential to distinguish these 2 clinically

similar entities.3 Patients with CBD may have atrophy of the cau-

date nucleus, putamen, and some cortical regions (premotor and

superior parietal), usually in an asymmetric pattern (Fig 1).24-26

Moreover, cerebral atrophy is substantially greater than that seen

in the clinically similar syndrome of progressive supranuclear

palsy.25 There may also be increased signal intensity within the

subcortical white matter.

Progressive Supranuclear Palsy. PSP, a tauopathy frequently in

the same differential diagnosis as CBD, may manifest early with

executive dysfunction or subcortical dementia and then progress

to involve the classic clinical presentation of supranuclear gaze

palsy and motor symptoms.27 Classically described MR imaging

findings typical of PSP were reviewed by Stamelou et al28 and

include the classic “humming bird” or “penguin” sign (Fig 2).24

These findings are largely related to atrophy within the midbrain,

with involvement of the midbrain, pons, thalamus, superior cer-

ebellar peduncle, and striatum; there may be hypointensity of the

putamen on T2-weighted sequences.25,28 Of clinical importance,

midbrain atrophy on MR imaging correlates with motor defi-

cits.29 Commensurate with midbrain atrophy, there may be dila-

tion of the third ventricle.28 There may also be T2-weighted hy-

perintensity of the tegmentum, corresponding to histopathologic

evidence of neuronal degeneration in this region; this sign appears

to be very specific, but not present in many cases.30

Because there is much overlap between PSP and CBD visually

on conventional MR imaging, many volumetric studies have at-

2 Degnan ● 2014 www.ajnr.org

tempted to delineate differences between the two, particularly

noting the lesser involvement of cortical atrophy in PSP.25,28,31

Also in the literature are less validated visual findings indicative of

PSP; a proposed imaging finding is an abnormal superior profile

of the midbrain on sagittal T1 images (Fig 3), in which the normal

convex profile of the midbrain becomes flattened or concave,

which is akin to the subjective hummingbird sign.30 DWI may

demonstrate increased putaminal ADC values, a finding that may

aid in differentiating PSP from Parkinson disease.32

Multiple-System Atrophy. The hallmark feature of this collec-

tion of neurodegenerative diseases of unknown cause, multiple-

system atrophy, is progressive cerebral atrophy, which has been

validated in small groups of patients with serial MR imaging

showing rapid atrophy corresponding with the duration of ill-

ness.33 Atrophic changes are noted by decreased size on conven-

tional imaging and hypointensity on T2-weighted imaging, par-

ticularly within the lower brain stem, middle cerebellar

peduncles, cerebellum, and putamen.26,34 In the pons, there is the

classic imaging finding of the “hot cross bun sign” (Fig 4).35-37

With this atrophy, there may be a surrounding hyperintense rim

seen on T2 images, which may appear before the hot cross bun

sign, but it is unfortunately nonspecific, with atrophy being more

important in distinguishing MSA from Parkinson disease.36,38

T2* gradient-echo signal loss within the dorsolateral putamen

reflective of increased iron deposition is highly specific for MSA,

but not always present.39 Serial MR imaging has been used to

characterize the atrophy noted within the pons, being particularly

good at distinguishing MSA and CBD with a 3-fold greater atro-

phy rate, both of which can be differentiated on this basis from

Parkinson dementia and healthy controls.29

DWI may demonstrate increased diffusivity and ADC within

the affected middle cerebellar peduncles, and other authors report

decreased fractional anisotropy matching this finding.34,40-42

Putaminal ADC increases likewise exist in MSA, but not Parkin-

son disease, and these values also correlate with clinical mea-

sures.41,43-46 Therefore, DWI and DTI are essential in improving

differentiation between MSA and other similar conditions such as

PSP and Parkinson disease.

Huntington Disease. Because of the CAG triplet repeat propa-

gated in an autosomal dominant fashion, clinicians diagnose HD

on the basis of genetic testing prompted from a family history of

early dementia and extrapyramidal symptoms with the hallmark

of chorea. Clinically, there is mounting evidence for preclinical

cognitive decline preceding any of the motor symptoms of HD.47

Classic imaging findings reveal atrophy of the caudate nucleus,

with concomitant enlargement of the frontal horns of the lateral

ventricles.26 This reduced size of the caudate nucleus has been

correlated with cognitive performance and precedes motor symp-

toms by many years (Fig 5).47,48 There may be T2 hyperintensity

in the region of the caudate nucleus with this atrophy. Moreover,

the basal ganglia may be hypointense on FLAIR and T2-weighted

FIG 1. Corticobasal degeneration. Imaging performed in an 84-year-old woman with corticobasal degeneration proved on postmortem exam-ination. A, Axial T2-weighted image shows right-side-dominant atrophy, including the central sulcus (arrow). B, Postmortem examination of thispatient’s brain shows right-frontal-dominant atrophy (arrow).24

FIG 2. Hummingbird or penguin sign. Imaging performed in a 74-year-old man with PSP. T1-weighted midsagittal image clearly shows atro-phy of themidbrain tegmentum (arrow), referred to as the humming-bird or penguin sign. The area of themidbrain tegmentum is 71 mm2.24

AJNR Am J Neuroradiol ●:● ● 2014 www.ajnr.org 3

A B C

CONVEX LINEAR CONCAVE

FIG 3. Abnormal superior profile of the midbrain in progressive supranuclear palsy. Top row: midsagittal T1-weighted spin-echo sections inParkinson disease (A) and PSP (B and C) show the midbrain region. Bottom row: images with outlined profiles of the upper midbrain, whichappears convex in A, linear (flat) in B, and concave in C as a result of midbrain atrophy in PSP.30

FIG 4. Hot cross bun sign. A 48-year-oldwomanwith spinocerebellar ataxia type 6. T2-weighted fast spin-echoMR image (TR/TE/TI, 3600/102/2ms) shows bilateral symmetric hyperintensity of atrophic middle cerebellar peduncles. The pons with the “cross sign” and cerebellum are alsoatrophic, as can be seen in multiple-system atrophy.35

FIG 5. Caudate atrophy in Huntington disease. A, Illustration of the fitted relationship between caudate volume and age in normal aging (blue)and patientswithHuntington disease according to disease duration (gray) formale subjectswith a total intracranial volumeof 1500mL. The blackline shows the predicted trajectory (with the 90% confidence interval [CI] in thick gray) for a patient with HD with motor onset at 45 years ofage. B, Fitted difference (with 90% CI) in caudate volume between patients with HD and controls according to disease duration. The differenceis statistically significant (P� .05, 1-sided)�14 years before motor onset.48

4 Degnan ● 2014 www.ajnr.org

images due to iron deposition, and this finding is thought to con-

stitute an early biomarker for the disease.49 Other advanced MR

imaging methods such as MR spectroscopy at a high-field

strength may aid in showing changes associated with HD with

decreased NAA and creatine within the caudate nucleus and

putamen.50

Neuroimaging may prognosticate the onset of disease progres-

sion in HD before the development of symptoms. A recent volu-

metric MR imaging study of patients before the clinical onset of

HD symptoms noted that patients who would develop symptoms

in 1– 4 years following their scans demonstrated significantly

smaller striatal volumes when they were still asymptomatic, par-

ticularly within the putamen.51 Other authors suggested that MR

imaging can detect striatal atrophy even up to 20 years before

motor deficits.52 This reduction in striatal volume was previously

hypothesized to serve as a biomarker for likely clinical progression

of HD.53 Others have defined more global atrophy in cortical

structures, perhaps later in the disease process, and these findings

are more inconsistent than those involving the striatum.52 From

the wealth of clinical studies performed to date, MR imaging has a

powerful role in the diagnosis and prognostication of HD.

ConclusionsThis first installment of a 2-part review of MR imaging findings in

the diverse clinical manifestation of rapidly progressive dementia

discussed the use of neuroimaging in diagnosing neurodegenera-

tive conditions, ranging from the common aging-associated de-

mentias to uncommon presentations of less prevalent conditions

such as multiple-system atrophy. Newer technologies, such as

amyloid imaging, may aid in distinguishing more unusual neuro-

degenerative causes of rapid cognitive decline and variants of the

more common Alzheimer dementia. MR imaging with selective

use of DWI, DTI, and MR spectroscopy is essential to narrow the

differential diagnosis on the basis of the subtle differences be-

tween neurodegenerative dementias, and it plays a key role in

establishing the diagnosis. The second part of this review will de-

tail the imaging findings seen in a wide range of other causes of

rapidly progressive dementia, including prion, infectious, inflam-

matory, autoimmune, neoplastic, metabolic, and nutritional

conditions.

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